Polyoxyethylene having a sugar on one end and a different functional group on the other end and a method of production thereof

ABSTRACT

This invention provides a heterotelechelic oligomer or polymer which is represented by the following formula: wherein A denotes a sugar residue, L denotes a linkage group represented by the following formula wherein R1 and R2 independently denote lower alkyl, aralkyl or aryl, X denotes a single bond or -CH2CH2-, Z denotes a group forming an unsaturated ester or ether, or a functional group such as halogen which binds to -CH2CH2-, n denotes an integer of 5-10,000, and m denotes an integer of 0 or 2-10,000. This invention also provides a process to produce the above oligomer or polymer, and further a high molecular-micelle with use of a polyethylene oxide-polyester block polymer which has a sugar residue at its terminal. Said oligomer or polymer is expected to exhibit excellent bioavailability, and is also expected to be utilized in the field such as carriers for drug delivery or diagnostic reagents.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a divisional of application Ser. No.08/930,855 filed Dec. 8, 1997 and now U.S. Pat. No. 5,973,069.

FIELD OF THE INVENTION

The present invention relates to an oligomer or polymer(heterotelechelic oligomer or polymer) which has a sugar on one end anda different functional group on the other end, and a method for theproduction of said oligomer or polymer.

PRIOR ARTS

Polyethyleneoxide has properties such as solubility in water andnon-immunogenicity, and its applications in biology and medicalengineering are noted, such as its use as a modifier of biologicallyactive substances such as proteins and drugs.

For example, it is known that when protein is modified with polyethyleneglycol, its immunogenicity is markedly reduced (Protein Hybrid, YujiInada, Hirotomo Maeda and Kyoritsu Shuppan (1988)). When thepolyethylene oxide is bonded to protein in this way, a function group toreact with the protein terminal must be on the end of the polyethyleneoxide. Generally, various functional groups such as carboxyl group,amino group, hydroxyl group and mercapto group are present on thesurface of a protein, and the selection of the functional group whenreacting with the polyethylene oxide often has a great influence on thephysiological activation of that protein.

Currently, most of the polyethylene oxide derivatives which are beingengineered have a hydroxyl group on both ends, or a non reactive alkoxygroup on one end and a hydroxyl group on the other end. Since thehydroxyl group has low reactivity compared to the aldehyde group and theamino group, there have been attempts to convert it to anotherfunctional group (Synth. Commun., 22(16), 2417-2424 (1992); J. Bioact.Compat. Polym., 5(2) 227-231 (1990). The manner of the reaction or useof polyethylene oxide has been disadvantageously limited when it isutilized as a modifier of protein in the above-mentioned way.

Furthermore, the importance of the hetero bonding to link a proteinhaving a certain function with a compound having another function suchas an antibody via polyethylene oxide has recently been noted. In thiscase, the polyethylene oxide derivative having a different functionalgroups on both ends is important. The method using a polyethylene oxidehaving a hydroxyl group at both ends as the raw material is used inorder to synthesize this type of heteropolyethylene oxide (Poly(ethyleneglycol) Chemistry; JM/Harris, Plenum Press, 1992). The product obtainedby this type of method is, however, a mixture of unreacted matter, sidereaction matter and over reaction matter modified on its both ends, and,therefore, this product needs to be refined by column operation or thelike so that the desired product may be isolated, which process causes alarge problem with yield and purity.

To overcome these types of problems, the inventors recently polymerizedpolyethylene oxide with an alkali metal salt of amino or alcohol havinga function group as an initiator, and discovered a method to synthesizeheteropolyethylene oxide quantitatively having different functionalgroups on both ends such as amino group, aldehyde group, mercapto group,carboxyl group and hydroxyl group (Japanese Patent Application No.5-009168; Tokugan 5-194977; Tokugan 6-94532; Tokugan 6-117262; andTokugan 6-228465)

However, quantitative synthesis of heteropolyethylene oxide having asugar residue on one end has ot yet been performed. Because of thecharacteristic interaction and affinity between the type of sugar andeach component in the body, a compound having a characteristic affinityfor biological components and having high bioavailability can beattained if a sugar group can be quantitatively introduced to one end ofpolyethylene oxide and a reactive functional group to the other end;such a compound would be a material which can be expected to be appliedto carriers for drug delivery which have targeting properties and toprecursors of diagnostic materials and the like.

The objective of this invention is therefore to produce a(heterotelechelic) polyethylene oxide derivative and apolyoxyethylene-polyester derivative having a sugar residue on one endand a reactive functional group other than sugar at the other end and toprovide a method to produce such derivatives selectively and with easeand efficiency.

DISCLOSURE OF THE INVENTION

The inventors of this invention have found that, by meas of applyingliving polymerization to sugars whose hydroxyl groups are selectivelyprotected and to ethylene oxide and lactone or lactide as cyclicmonomers, there can be freely produced heterotelechelic oligomer andpolymer which have a sugar on one end and a reactive functional groupother than sugar on the other end and which have a narrow molecularweight distribution and which have a desired polymerization degree. Thusproduced polyethylene oxide derivative is expected to show excellentbioavailability and to be conveniently used as a material or precursorin the field of biochemistry and/or medical treatment.

This invention provides a polyethylene oxide derivative which isrepresented by the following formula (I): ##STR3## wherein A denotes asugar residue represented by the following formula ##STR4## wherein thegroups R independently denote the followings: one of the Rs denotes alinkage of covalent bond with the adjacent methylene group via oxygenatom; as for the other Rs, they sometimes denote hydrogen atom, C₁₋₅alkyl, C₁₋₅ alkylcarbonyl or tri-C₁₋₅ alkylsilyl (these alkyls aresimilar or different), and, sometimes, two of said Rs in combination,while forming an acetal together with the oxygen atom to which the Rsare bound, denote C₃₋₅ alkylidene or benzylidene whose methine may besubstituted with C₁₋₃ alkyl; a denotes an integer of 0 or 1, b denotesan integer of 2 or 3, and c denotes an integer of 0 or 1,

n denotes an integer of 5-10,000,

L denotes a linkage group represented by the following formula ##STR5##wherein R¹ and R² independently denote hydrogen atom, C₁₋₆ alkyl, arylor C₁₋₃ alkylaryl,

m denotes an integer of 0 or 2-10,000,

X denotes a single bond or --CH₂ CH₂ --, and

when X is a single bond, Z denotes hydrogen atom, alkali metal,acryloyl, methacryloyl, cinnamoyl, p-toluenesulfonyl, allyl,carboxymethyl, carboxyethyl, ethoxycarbonylmethyl, ethoxycarbonylethyl,2-aminoethyl, 3-aminopropyl, 4-aminobutyl, vinylbenzyl, di-C₁₋₅alkyloxy-C₂₋₃ alkyl or aldehyde-C₂₋₃ alkyl, while, when X is --CH₂ CH₂-- and m is O, Z denotes hydroxyl, mercapto, amino or halogen atom.

In another aspect, this invention provides a process to produce apolyethylene oxide derivative represented by the above formula (I) whichprocess comprises the following steps:

Step (1):

Ethylene oxide is polymerized in the presence of a polymerizationinitiator represented by the following formula (II) ##STR6## wherein thegroups R independently denote the followings: one of the Rs denotes analkali metal (M), e.x., sodium, potassium or cesium; as for the otherRs, they sometimes denote C₁₋₅ alkyl, C₁₋₅ alkylcarbonyl or tri-C₁₋₅alkylsilyl (these alkyls are similar or different), and, sometimes, twoof said Rs in combination, while forming an acetal together with theoxygen atom to which the Rs are bound, denote C₃₋₅ alkylidene orbenzylidene whose methine may be substituted with C₁₋₃ alkyl; a denotesan integer of 0 or 1, b denotes an integer of 2 or 3, and c denotes aninteger of 0 or 1.

Step (2):

If need be, the oligomer or polymer obtained in the above Step (1)represented by the following formula (III) ##STR7## wherein A and n areas defined in formula (I) is either

(i) hydrolyzed

or

(ii) made to react with ##STR8## wherein R¹ and R² are as defined informula (I) so that there may be obtained oligomer or polymerrepresented by the following formula (IV) ##STR9## wherein A, L, m and nare as defined in formula (I). Step (3):

If necessary, the oligomer or polymer obtained in Step (1) or Step (2)is made to react either with

(i) acrylic acid, methacrylic acid, p-toluenesulfonic acid or reactivederivative thereof

or with

(ii) the halide represented by the following formula (V)

    halo-E                                                     (V)

wherein halo denotes chlorine, bromine or iodine, E denotes allyl,carboxymethyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, vinylbenzyl,N-phthalimide ethyl, N-phthalimide propyl or N-phthalimide butyl.

Step (4):

If necessary, groups R of the sugar residue A are eliminated except theabove-mentioned likage.

In the above-stated manner, this invention provides a novelheterotelechelic polyethylene oxide or polyyethylene oxide-polyesterderivative represented by formula (I) which is mono-dispersible ormono-modal polymer or oligomer having any polymerization degreedepending on objective, and the invention also provides a method toefficiently produce said polymer or oligomer.

The derivative represented by formula (I) can be used as a carrier forthe support or drug delivery of various kind of medicines. When suitableprotein, for example, antibodies and the like, are bound via functionalgroup of the derivative, said derivative is expected to be usable as acarrier having targeting properties for a medicine or as a diagnosticreagent.

In particular, the derivative wherein m in formula (I) denotes aninteger of 2-10,000, has usability as a carrier for supporting medicinessince such a derivative forms a stable high molecular micelle in anaqueous solvent.

BRIEF EXPLANATION OF FIGURES

FIG. 1 shows a gel permeation chromatogram of the heterotelechelicpolyethyleneoxide (i.e., the sample of Example 1 mentioned later) whichquantitatively has a 1,2;5,6-di-O-isopropylidene-D-glucofuranose residueat the α-terminal and a hydroxy group at ω-terminal (Condition: Column:TSK-Gel (G4000 H×L, G3000 H×L, G2500 H×L); Eluent: THF (containing 2%triethylamine); Flow rate: 1 ml/min.)

FIG. 2 shows proton nuclear magnetic resonance spectra of theheterotelechelic polyethyleneoxide (i.e., the sample of Example 1mentioned later) which quantitatively has a1,2;5,6-di-O-isopropylidene-D-glucofuranose residue at α-terminal and ahydroxy group at ω-terminal.

FIG. 3 shows a gel permeation chromatogram of the heterotelechelicpolyethyleneoxide (the sample of Example 2 mentioned later) whichquantitatively has a3,5-O-benzylidene-1,2-O-isopropylidene-D-glucofuranose residue atα-terminal and a hydroxy group at ω-terminal (operational condition isthe same as in FIG. 1).

FIG. 4 shows proton nuclear magnetic resonance spectra of theheterotelechelic polyethyleneoxide (the sample of Example 2 mentionedlater) which quantitatively has a3,5-O-benzylidene-1,2-O-isopropylidene-D-glucofuranose residue atα-terminal and a hydroxy group at ω-terminal.

FIG. 5 shows a gel permeation chromatogram of the heterotelechelicpolyethyleneoxide (the sample of Example 3 mentioned later) whichquantitatively has a 1,2;3,4-di-O-isopropylidene-D-galactopyranoseresidue at α-terminal and a hydroxy group at ω-terminal (operationalcondition is the same as in FIG. 1 except that THF was used as aneluent).

FIG. 6 shows proton nuclear magnetic resonance spectra of theheterotelechelic polyethyleneoxide (the sample of Example 3 mentionedlater) which quantitatively has a1,2;3,4-di-O-isopropylidene-D-galactopyranose residue at α-terminal anda hydroxy group at ω-terminal.

FIG. 7 shows proton nuclear magnetic resonance spectra of glucose (thesample of Example 4 mentioned later) which quantitatively has apolyethyleneoxide chain at the hydroxyl group on the 6-position.

DETAILED DESCRIPTION OF THE INVENTION

The group A in the polyethylene oxide derivative of formula (I) of thisinvention may be either made from a natural product or a derivative of anatural product or a chemical synthetic so long as it is a residue ofmonosaccha-ride represented by the formula ##STR10## wherein R, a, b andc are as defined above.

Examples of sugars from natural products from which such a sugar residuecan be conveniently derived include, not restrictively, the followings:glucose, galactose, mannose, fructose, ribose, arabinose, xylose,lyxose, allose, altrose, gulose, idose and talose. What is mostpreferable among these varies dependent on the object of use of thepolyethylene oxide derivative of this invention, and, therefore, cannotbe limited. From the viewpoint of availability of raw material, however,glucose, galactose, mannose, fructose, ribose and xylose are generallypreferable. From such a viewpoint, glucose and galactose are especiallypreferable.

The groups R in the above sugar residue, which are intended to protectall the hydroxyl groups of the sugar residue, subjecting the derivativeof formula (I) to further reactions, are either such groups as arecapable of selective deprotection when necessary or hydrogen atoms,except the single R which is a linkage of covalent bond of said sugarresidue with the α-terminal methylene group of the polyethylene oxidesegment of the derivative of formula (I) via oxygen atom to which said Ris bound. Concrete examples of such protecting group include C₁₋₅ alkyl,C₁₋₅ alkylcarbonyl and tri-C₁₋₅ alkylsilyl groups. The alkyl portion ofthese groups may be straight chain or branched chain alkyl, for example,methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, tert-butyl, pentyland iso-pentyl. As for tri-C₁₋₅ alkylsilyl, three alkyl portions thereinmay be similar or different. Preferable examples of this group includetri-methylsilyl, triethylsilyl and tripropylsilyl wherein the alkylportions therein are similar to one another.

In another case, two of said Rs in combination, while forming an acetal##STR11## together with the oxygen atom to which the Rs are bound,denote C₃₋₅ alkylidene such as isopropylidene, 1-butylidene,2-butylidene or 3-pentylidene, and benzylidene whose methine may besubstituted with C₁₋₃ alkyl such as benzylidene ##STR12## andmethylbenzylidene ##STR13##

When two Rs form these acetals, these groups R can be selectivelyeliminated with ease, and there can be conveniently produced a sugarresidue wherein R denotes hydrogen atom (hydroxyl group is deprotected).

The marks a, b and c in the above formula denote integers which varyaccording to the kind of sugar selected as a starting material The marka is 0 or 1, b is 2 or 3, and c is 0 or 1. When glucose is used as astarting material, for example, a is 0, b is 3 and c is 0 in the case ofD-gluco-pyranose in the form of intramolecular hemiacetal, while, in thecase of D-glucofuranose, a is 0, b is 2 and c is 1. Both of these formsare therefore included in the above sugar residue.

When galactose is used as a starting material, on the other hand, a is0, b is 3 and c is 0.

The mark n in the segment ##STR14## derived from ethylene oxide informula (I) can theoretically be any number when the proportion of theamount of ethylene oxide (monomer) to polymerization initiator isadjusted in the production method of this invention by means of livingpolymerization. In order to achieve the object of this invention, n ispreferably be an integer of 5-10,000.

When n is less than 5, it is generally difficult to keep narrow themolecular weight distribution of oligomer (or polymer) having such anumber n, and, thus, it may be hard to produce mono-dispersible ormono-modal oligomer (or polymer).

On the other hand, n is an integer of at most 10,000. As stated above,the production method of this invention can theoretically provide apolymer of higher polymerization degree. When the polyethylene oxidederivative of this invention is to be used as a precursor for a carrierto support medicines or the like, however, n is preferably be not higherthan 10,000.

Incidentally, it should be understood that the inventors contemplateusing the derivative of this invention as an intermediate from which toextend further oxyethylene or ester segments. More concretely, however,n in the derivative of formula (I) of this invention is preferably aninteger of 10-200, more preferably, 20-50.

The mark L in the segment (also called polyester segment) derived fromlactide or lactone of formula (I) ##STR15## denotes ##STR16## or##STR17##

The above R¹ and R² independently denote hydrogen atom, C₁₋₆ alkyl, arylor C₁₋₃ alkyl aryl.

Examples of C₁₋₆ alkyl include straight chain or branched chain loweralkyl group such as methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl,tert-butyl pentyl, iso-pentyl and hexyl. Preferable example of aryl isphenyl, and examples of C₁₋₃ alkylaryl include benzyl, ethyl benzene andthe like.

These segments are usually derived from lactide of α-hydroxycarboxylicacid. In consideration of bioavailability, they are preferably derivedfrom glycolic acid, lactic acid, 2-hydroxyisobutyric acid or such alactide as comprises two of these in combination. In other words, it ispreferable that R¹ and R² independently denote hydrogen atom, methyl orisopropyl group.

The segment ##STR18## is optional. The mark m may denote 0 (said segmentis absent) or an integer of 2-10,000, and may form a block polymer. Whena block polymer is formed, this segment generally provides thepolyethylene oxide derivative of this invention with a hydrophobicportion. The preferable size of m is therefore dependent on the objectof use of the derivative (block polymer) of this invention or on theproperties of the groups R¹ and R² Generally, however, m is preferably5-200, more preferably, 10-100.

The mark X in --X--Z in formula (I) is either a single bond in the casewhere Z is directly covalently bound to the oxygen atom at ω-position ofthe following segments ##STR19## or ##STR20## or ethylene (--CH₂ CH₂--). Therefore, when m is 0, this ethylene group can be derived from--CH₂ CH₂ --OH which is formed on account of the addition of ethyleneoxide.

When X is a single bond, Z can be hydrogen atom or alkali metal. In thiscase, the compound of this invention is provided as a reaction productor its hydrolyzate from a living polymerization wherein there are usedthe anion of the sugar residue A as a polymerization initiator, ethyleneoxide as a monomer, and, according to circumstances, lactide or lactone.Typical examples of alkaline metal therefore include sodium, potassiumand cesium.

When Z is other than alkali metal and hydrogen atom, the polyethyleneoxide derivative of this invention provides various kind of ether andester having a different functional group which is formed via theω-terminal hydroxyl group. Z can therefore be a group which is capableof forming ester such as acryloyl (--COCH═CH₂), methacryloyl(--COC(CH₃)═CH₂), cinnamoyl ##STR21## and p-toluenesulfonyl ##STR22##

On the other hand, examples of such Z as can form an ether include allyl(--CH₂ --CH═CH₂), carboxymethyl (--CH₂ COOH), carboxyethyl (--CH₂ CH₂COOH), ethoxycarbonylmethyl (--CH₂ COOC₂ H₅ ), ethoxycarbonylethyl(--CH₂ CH₂ COOC₂ H₅), 2-aminoethyl (--CH₂ CH₂ NH₂), 3-aminopropyl (--CH₂CH₂ CH₂ NH₂), 4-aminobutyl (--CH₂ (CH₂ )₂ CH₂ NH₂) and vinylbenzyl##STR23## and di-C₁₋₅ alkyloxy-C₂₋₃ -alkyl such as 2,2-dimethyloxyethyl(--CH₂ CH(OCH₃)₂), 2,2-diethoxyethyl (--CH₂ CH(OC₂ H₅)₂) and3,3-dimethoxypropyl (--CH₂ CH₂ CH(OCH₃)₂), and aldehyde-C₂₋₃ alkyl(--(CH₂)₁₋₂ CHO).

Furthermore, when X denotes --CH₂ CH₂ -- and m denotes 0 (zero), Z canbe hydroxyl, mercapto (--SH), amino (--NH₂) and halogen such aschlorine, bromine and iodine. The derivative of formula (I) having thesesubstituents can be obtained from ω-terminal p-toluene sulfonatedcompound through a known reaction.

The following Table 1 shows concrete examples of polyethylene oxidederivatives (compounds) of this invention which are composed of theabove-mentioned substituents.

                                      TABLE 1                                     __________________________________________________________________________      #STR24##                                                                       -                                                                            Compound  No. A Site of  sugar  linkage n-1                                                                         m X Z5##                              __________________________________________________________________________    1     Glu(p)*.sup.1)                                                                     3-0 20˜50                                                                       --        0 --     H                                         2 Glu(p) 3-0 20˜50 -- 0 -- K                                            3 Glu(p) 3-0 20˜50 -- 0 -- COC(CH.sub.2)═CH.sub.2                   4 Glu(p) 3-0 20˜50 -- 0 -- COCH═CH.sub.2                            5 Glu(p) 3-0 20˜50 -- 0 --                                                                                    #STR26##                                 - 6 Glu(p) 3-0 20˜50 -- 0 -- CH.sub.2 --CH═CH.sub.2                7 Glu(p) 3-0 20˜50 -- 0 -- CH.sub.2 COOC.sub.2 H.sub.5                  8 Glu(p) 3-0 20˜50 -- 0 -- CH.sub.2 CH.sub.2 COOC.sub.2 H.sub.5                                              9 Glu(p) 3-0 20˜50 -- 0 --                                             CH.sub.2 CH.sub.2 NH.sub.2                10 Glu(p) 3-0 20˜50 -- 0 --                                                                                   #STR27##                                 - 11 Glu(p) 3-0 20˜50 -- 0 -- CH.sub.2 CHO                             12 Glu(p) 3-0 20˜50 -- 0 -- CH.sub.2 CH.sub.2 CHO                       13 Glu(p) 3-0 20˜50 -- 0 --CH.sub.2 CH.sub.2 -- Cl                      14 Glu(p) 3-0 20˜50 -- 0 --CH.sub.2 CH.sub.2 -- SH                    15˜22                                                                        Deprotected*.sup.2) compounds corresponding to Compound Nos. 1, 3,            4, 6, 9, 10, 13 and 14                                                   23   Glu (deprotected)                                                                        3-0  20˜50                                                                          --   0    --   CH.sub.2 COOH                        24 Glu (deprotected) 3-0 20˜50 -- 0 -- CH.sub.2 CH.sub.2 COOH                                                     25 Glu (deprotected) 3-0                                                     20˜50 -- 0 -- CH.sub.2                                                  CHO                                  26 Glu (deprotected) 3-0 20˜50 -- 0 -- CH.sub.2 CH.sub.2 CHO          27˜52                                                                        Compounds corresponding to Compound Nos. 1˜26, wherein site of          sugar linkage is 6-0                                                       53˜66 Compounds corresponding to Compound Nos. 1˜14,                 wherein Glu(p) is Gal(p) and the site of sugar linkage is 6-0                  67˜74 Compounds corresponding to Compound Nos. 1, 3, 4, 6, 9,          10, 13 and 14, wherein Glu(p) is Gal(deprotected) and the                   site of sugar linkage is 6-0                                                 75˜78 Compounds corresponding to Compound Nos. 23˜26,                wherein Glu(deprotected) is Gal(deprotected) and the site of                    sugar linkage is 6-0                                                     79˜92 Compounds corresponding to Compound Nos. 1˜14,                 wherein Glu(P) is Man(P)*.sup.4) and the site of sugar                      linkage is 4-0                                                               93˜100 Compounds corresponding to Compound Nos. 1, 3, 4, 6, 9,             10, 13 and 14, wherein Glu(p) is Man(deprotected) and                       the site of sugar linkage is 4-0                                             101˜104 Compounds corresponding to Compound Nos. 23˜26,              wherein Glu(deprotected) is Man(deprotected)                                and the site of sugar linkage is 4-0                                       105  Glu(p)                                                                             3-0                                                                              20˜50                                                                         ##STR28##       20˜100                                                                       -- H                                     - 106 Glu(p) 3-0 20˜50                                                                                            20˜100 -- K                   - 107 Glu(p) 3-0 20˜50                                                                                            20˜100 -- H                   - 108 Glu(p) 3-0 20˜50                                                                                            20˜100 -- K                   - 109˜118 Gal(p) 6-0 20˜50                                                                                  20˜100 -- Groups                                                      corresponding to  Compound                                                    Nos. 3˜12                       -                                                                          119˜128                                                                      Compounds corresponding to Gal (deprotected) of Compound Nos.                 109˜118                                                              129˜132 Compounds corresponding to Compound Nos. 105˜108,            wherein site of sugar linkage is 6-0                                     __________________________________________________________________________     Note                                                                          *.sup.1) Glu(P) means that the hydroxyl groups other than those at the        3position of glucose are protected with isopropylidene group.                 *.sup.2) "deprotected" means that isopropylidene group or benzylidene         group is eliminated to form a hydroxyl group.                                 *.sup.3) Gal(P) mean that the hydroxyl groups other than those at the         6position of galactose are protected with 1,2di-isopropylidene group.         *.sup.4) Man(P) means that the hydroxyl groups other than those at the        4position of mannose are protected with isopropylidene group.            

The polyethylene oxide derivatives provided by the present invention canbe produced efficiently by the process of this invention which comprisesthe following steps:

Step (1):

Alkali metal (e.x., sodium, potassium or cesium) glycoside of formula(II) ##STR33## wherein R, a, b and c are as defined above is subjectedto living polymerization with ethylene oxide as a reaction initiator.

The alkali metal glycoside of formula (II) can be produced by protectinghydroxyl groups of a monosaccharide except one hydroxyl group and thenmetallizing the mono-saccharide. This metallization can be achieved byusing, as a metallizer, alkali metal such as sodium and potassium,organic metal such as sodium naphthalene, potassium naphthalene, cumylpotassium, cumyl cesium, and metal hydroxide such as sodium hydroxideand potassium hydroxide.

Thus obtained compound of formula (II) can preferably be made to reactwith ethylene oxide either in the absence of solvent or in an anhydrousaprotic solvent within a wide range of temperature of -50° C. to 300°C., preferably 10° C. to 60° C., conveniently at a room temperature (20°C. to 30° C.). The reaction may be conducted either under pressure orunder reduced pressure. Usable solvents, although not restricted,include benzene, toluene, xylene, tetrahydrofuran and acetonitrile.Usable reactors, although not restricted in particular, includeround-bottomed flask, autoclave and pressure resistant sealed tube. Thereactor is preferably airtight, and is more preferably filled with inertgas. Reaction solution has a concentration of 0.1 to 95% by weight,preferably 1 to 80% by weight, most preferably 3 to 10% by weight.

Thus obtained polymer of formula (III) is itself included in thederivatives of formula (I) of the present invention. Furthermore, whenthe polymer is hydrolyzed or when the protecting group of hydroxyl iseliminated from sugar residue, there can be provided a derivative of thepresent invention wherein m denotes 0 and --X--Z denotes hydrogen atomin formula (I).

Step (2):

An oligomer or polymer represented by formula (III) ##STR34## wherein Aand n are as defined above, and M denotes sodium, potassium or cesium isallowed to react with a cyclic monomer represented by the followingformula: ##STR35## wherein R¹ and R² are as defined above.

Although reaction temperature is not restricted, this step can beperformed at a room temperature as in Step (1). Moreover, this step canbe achieved by adding a cyclic monomer to the reaction mixture of Step

The amount of monomer used in Steps (1) and (2) can be adjustedaccording to the polymerization degree which is shown by the numberdenoted by n and m in the desired formula (I). In Step (1), for example,the proportion of the compound of formula (II) to ethylene oxide usedis, in molar ratio, 1:1 to 1:10,000, preferably 1:5 to 1:10,000, mostpreferably 1:20-200 to 1:50-200.

Step (3):

The block oligomer or polymer of formula (IV) obtained in Step (2) isitself included in the derivatives of formula (I) of the presentinvention. Furthermore, when said oligomer or polymer is hydrolyzed or,under circumstances, when protecting groups of hydrogyl groups in thesugar residue are eliminated, there can be provided the derivatives ofthe present invention wherein m in formula (I) denotes an integer of2-10,000 and --X--Z denote a hydrogen atom.

In Step (3), the alkali metal alkoxide of the above formula (III) or(IV) is hydrolyzed to become an ω-terminal hydroxyl body, which is (i)made to react with acrylic acid, methacrylic acid or p-toluene sulfonicacid in an inert organic solvent to form an ω-terminal esterifiedcompound, or (ii) allowed to react with a halide of formula (V)

    halo-E                                                     (V)

wherein halo and E are as defined above to form an ω-terminal etherifiedcompound.

These reactions can be carried out by known esterification oretherification process. Concrete processes are shown in Examplesmentioned later. As for the organic acid in the above (i), there areconveniently employed reactive derivative of acid anhydride or acidhalide.

In the case of introducing a mercapto group to the ω-terminal forexample, after the tosylation of the ω-terminal of hydrolyzate offormula (III) or (IV) with p-toluenesulfonylchloride, thioester group isintroduced to the ω-terminal by the reaction with an electrophilic agentsuch as sodium thioacetate, potassium thioacetate, or potassiumhydrosulfide; then hydrolysis of the ω-terminal thioester is performedat the same time as deprotection of the sugar residue by processing withan alkali or acid, and the compound shown in formula (I) is attained.Also, another method to attain the compound shown in formula (I) is thecoupling reaction of the hydrolyzate of formula (III) or (IV) with ap-toluenesulfonic acid ester having an S--S bond such as dithiodiethanolditosylate, then a reducing reaction to attain a mercapto terminalgroup, followed by deprotection of the sugar residue by processing withan acid or alkali.

In the case of introducing an amino group to the ω-terminal for example,the hydrolyzate of formula (III) or (IV) is reacted with anelectrophilic agent, N-(2-bromoethyl)phthalimide,N-(3-bromopropyl)phthalimide, 1-bromo-2-(benzeneamide)ethane,N-(2-bromoethyl)benzyl carbamate; then hydrolysis of the ω-terminalimide bond is performed at the same time as de-protection of the sugargroup by processing with an alkali or acid, and the compound shown informula (I) is attained.

In the case of introducing an aldehyde group to the ω-terminal forexample, a halogenated alkyl having an acetal group such as2,2-dimethoxyethylchloride, 2,2-diethoxyethylchloride,2,2-dimethoxyethylbromide, 2,2-diethoxyethylbromide, or3,3-dimethoxypropylchloride is reacted; then hydrolysis of theω-terminal acetal is performed at the same time as deprotection of thesugar residue by processing with an alkali or acid, and the compoundshown in formula (I) is attained.

Step (4):

When the protecting groups of the sugar residue are eliminated ifnecessary, the oligomer or polymer obtained in the above provides thederivatives of formula (I) of the present invention wherein theprotecting groups R (other than linkage) of the sugar residue areeliminated (resultantly, R denotes hydrogen atom). Two of the protectinggroups R preferably form an acetal together, so that the protectinggroups R are selectively eliminated. As for the eliminating reaction,acid hydrolysis with use of trifluoroacetic acid is convenient.

The reagent used during hydrolysis of R of the sugar residue andprotecting groups (when the group Z has protecting groups) of the otherportions may be an acid such as hydrochloric acid, sulfuric acid, nitricacid, formic acid and hydrogen fluoride, as well as the abovetrifluoroacetic acid or alkali such as sodium hydroxide and potassiumhydroxide. Also, reducing agent such as lithium aluminum hydride can beused.

In the method for hydrolysis, the polymer attained as above is dissolvedin 0.01N-10N, preferably 0.1N-5N acid or alkali. The reactiontemperature is 0-100° C., preferably 10-80° C., and most preferably20-40° C.; the reaction time is 1 minute to 200 hours, preferably 30minutes to 100 hours, and most preferably 1-2 hours.

With hydrolysis in this manner, the polyethylene oxide derivative shownin formula (I) and quantitatively having a sugar group on one end and afunctional group other than sugar on the other end can be selectivelyattained.

After the end of the reaction, polyethylene oxide derivative which isthe objective can be isolated as a precipitate by putting the reactionsolution in a solution in which the polyethylene oxide is not solublesuch as diethylether, isopropyl alcohol, or hexane. Also, it can beisolated and refined using methods such as dialysis, ultrafiltration,adsorbent processing, and the method with column chromatograms.

In this manner, the present invention provides mono-modal derivativesrepresented by formula (I) which have narrow molecular weightdistribution and desired molecular weight. These derivatives are novelheterotelechelic oligomers or polymers which are expected to haveexcellent bioavailability.

The following is concrete examples of the present invention. Theseexamples are, however, not intended to restrict this invention.

Typical reaction scheme:

For easy understanding of this invention, the following schemes show thereaction system for the synthesis of the hetero bivalentpoly(ethyleneglycol) having a reduced carbohydrate group on one end,this being a mode of this invention.

(Starting material: glucose) ##STR36## (Starting material: galactose)##STR37##

EXAMPLE 1

Preparation of 1,2;5,6-di-O-isopropylidene-D-glucofuranose-3-O-polyethylene oxide ##STR38##

(1) After D-glucose 100 g was dissolved in acetone 660 ml and zincchloride 80 g and 85% phosphoric acid aqueous solution 2.7 ml wereadded, this was reacted 32 hours at room temperature. After theunreacted D-glucose was filtered, the filtered solution was neutralizedwith 2.5 N sodium hydroxide aqueous solution. The salt was filtered outand vacuum hardened. The residue was dissolved in water 100 ml, theproduct was eluted with chloroform (100 ml×3), and after dehydration,this was vacuum hardened and a yellow solid was attained. This wasrecrystallized with ligroin and 1,2;5,6-di-O-isopropylidene-D-glucofuranose (DIG) of the following formulawas attained. The yield was 63.6 g (43.6%). ##STR39##

(2) DIG 260 mg. THF 20 ml, and potassium naphthalene 0.5mol/L-tetrahydrofuran solution 2 ml were added to the reactioncontainer, agitated for 3 minutes in an argon atmosphere, and3-O-potassium-1,2; 5,6-di-O-isopropyidene-D-glucofuranose was produced.Ethylene oxide 5.7 g was added to this solution and agitated at roomtemperature under 1 atm. After reacting for two days, a small amount ofwater was added and the reaction was stopped; then the reaction solutionwas poured into ether and the polymer produced was precipitated. Theprecipitate attained was refined by freeze drying from benzene. Theyield was 5.6 g (94%). The polymer attained through gel permeationchromatography was monomodal, the molecular weight of the polymer was2500 (FIG. 1).

According to the proton nuclear magnetic resonance spectra in thechloroform deuteride of the polymer attained, this polymer was confirmedto be heterotelechelic oligomer quantitatively having 1,2;5,6-di-O-isopropylidene-D-glucofuranose group on the α-terminal andhydroxyl group on the ω-terminal and having the polyethylene oxide (PEO)(FIG. 2). The number average molecular weight of the polymer determinedby the integral ratio of the spectra was 2400.

EXAMPLE 2

Preparation of3,5-O-benzylidene-1,2-O-isopropylidene-D-glucofuranose-6-O-polyethyleneoxide ##STR40##

(1) DIG 10 g was dissolved in methanol 40 ml, 0.8% sulfuric acid aqueoussolution 50 ml was added, and this was left standing at room temperaturefor 23 hours; then barium carbonate was added and this was neutralized,after boiling for 10 minutes, the salt was filtered out. Benzaldehyde 18ml and zinc chloride 6.0 g were added to the white sold attained (7.5 g)after solvent distillation and this was agitated fiercely for 6 hours atroom temperature. The sample attained was recrystallized from benzeneand the 3,5-O-benzylidene-glucofuranose (BIG) of the following formulawas attained. The yield was 1.8 g (17.5%). ##STR41##

(2) BIG 308 mg, THF 20 ml, and potassium naphthalene 0.5 mol/Ltetrahydrofuran solution 2 ml were added to the reaction container andagitated for 3 minutes in an argon atmosphere;6-O-potassium-3,5-O-benzylidene-1,2-O-isopropylidene-D-glucofuranose wasproduced. Ethylene oxide 5.3 g was added to this solution and agitatedat room temperature and 1 atom. After reacting for 2 days, a smallamount of water was added and the reaction was stopped; then thereaction solution was poured into ether and the polymer produced wasprecipitated. The precipitate attained was refined by freeze drying frombenzene. The yield was 3.5 g (63%). The polymer attained through gelpermeation chromatography was mono-modal, the number average molecularweight of the polymer was 1800 (FIG. 5).

According to the proton nuclear magnetic resonance spectra in thechloroform deuteride of the polymer attained, this polymer was confirmedto be heterotelechelic oligomer quantitatively having the3,5-O-benzylidene-1,2-O-isopropylidene-D-glucofuranose group on theα-terminal and hydroxy group on the ω-terminal and having thepolyethylene oxide (PEO) (FIG. 4). The number average molecular weightof the block polymer determined by the integral ratio of the spectra was2000.

EXAMPLE 3

Preparation of 1,2;3,4-di-O-isopropylidene-D-galactopyranose-6-O-polyethylene oxide##STR42##

(1) Galactose 50 g was dissolved in acetone 1 liter; copper sulfuricanhydride 100 g and concentrated sulfuric acid 5 ml were added and thiswas agitated and reacted for 24 hours at room temperature. After thereaction was completed, the unreacted material was filtered out and thefiltered solution was neutralized with calcium hydroxide aqueoussolution. The unnecessary salt was filtered out, then the solvent wasremoved under vacuum and vacuum distilled; the 1,2;3,4-di-O-isopropylidene-D-galactopyranose shown in the following formulawas attained. The yield was 35 g (48%). ##STR43##

The above compound 180 mg, THF 15 ml, and potassium naphthalene 0.5mol/L tetrahydrofuran solution 2 ml were added to the reaction containerand agitated for 3 minutes in an argon atmosphere; the6-O-potassium-1,2; 3,4-di-O-isopropylidene-D-galactopyranose wasproduced. Ethylene oxide 4.4 g was added to this solution and agitatedat room temperature and 1 atm. After reacting for 2 days, a small amountof water was added and the reaction was stopped; then the reactionsolution was poured into ether and the polymer produced wasprecipitated. The precipitate attained was refined by freeze drying frombenzene. The yield was 1.7 g (38%). The polymer attained through gelpermeation chromatography was mono-modal, the number average molecularweight of the polymer was 3500 (FIG. 5).

According to the proton nuclear magnetic resonance spectra in thechloroform deuteride of the polymer attained, this polymer was confirmedto be the heterotelechelic oligomer quantitatively having the 1,2;3,4-di-O-isopropylidene-D-galactopyranose group on the α-terminal andhydroxy group on the ω-terminal and having the polyethylene oxide (PEO)(FIG. 6). The number average molecular weight of the polymer determinedby the integral ratio of the spectra was 3300.

EXAMPLE 4

Preparation of the compound represented by the following formula##STR44##

The polyethylene oxide derivative 50 mg attained in Example 2 wasdissolved in 90 vol % trifluoroacetate and left standing 40 minutes atroom temperature. After the reaction, the solvent was vacuum distilledand refined with gel filtration. The yield was 47 mg (94%). According tothe proton nuclear magnetic resonance spectra in the chloroformdeuteride of the polymer attained, this polymer was confirmed to beglucose having a polyethylene oxide chain quantitatively on the6-position hydroxyl group, in which the peak of the benzylidene of thesugar group and the isopropylidene protective group disappearedcompletely, and which maintains the polyethylene oxide (PEO) unit (FIG.7).

EXAMPLE 5

Preparation of the compound represented by the following formula##STR45##

The polyethylene oxide derivative 50 mg attained in Example 1 wasdissolved in 90 vol % trifluoroacetate and left standing 40 minutes atroom temperature. After the reaction, the solvent was vacuum distilledand refined with gel filtration. The yield was 40 mg (80%). According tothe proton nuclear magnetic resonance spectra in the chloroformdeuteride of the polymer attained, this polymer was confirmed to beglucose having a polyethylene oxide chain quantitatively on the3-position hydroxyl group, in which the peak of the two isopropylideneprotective groups of the sugar group disappeared completely, and whichmaintains the polyethylene oxide (PEO) unit.

EXAMPLE 6

Preparation of the compound represented by the following formula##STR46##

The polyethylene oxide derivative 50 mg attained in Example 3 wasdissolved in 90 vol % trifluoroacetate and left standing 40 minutes atroom temperature. After the reaction, the solvent was vacuum distilledand refined with gel filtration. The yield was 45 mg (90%). According tothe proton nuclear magnetic resonance spectra in the chloroformdeuteride of the polymer attained, this polymer was confirmed to beglucose having a polyethylene oxide chain quantitatively on the6-position hydroxyl group, in which the peak of the isopropylideneprotective group and the benzylidene group of the sugar groupdisappeared completely, and which maintains the polyethylene oxide (PEO)unit.

EXAMPLE 7

Preparation of the compound represented by the following formula##STR47##

The compound 308 mg, THF 20 ml, and potassium naphthalene 0.5 mol/Ltetrahydrofuran solution 2 ml were added to the reaction container andagitated 3 minutes in an argon atmosphere;6-O-potassium-3,5-O-benzylidene-1,2-O-isopropylidene-D-glucofuranose wasproduced. Ethylene oxide 5.3 g was added to this solution and agitatedfor 2 days at room temperature and 1 atm. Dimethylsulfoxide solution 10ml including ethyl 2-bromopropionate acid ethyl 0.2 g was added to thisreaction solution and this underwent chemical modification in thereaction for 24 hours at room temperature. This solution was poured intoether and the polymer produced was precipitated . The precipitateattained was refined by freeze drying from benzene. The yield was 3.0 g(48%). The polymer attained through gel permeation chromatography wasmono-modal, the number average molecular weight of the polymer was 2000.

According to the proton nuclear magnetic resonance spectra in thechloroform deuteride of the polymer attained, it was confirmed to be aheterotelechelic oligomer quantitatively having3,5-O-benzylidene-1,2-O-isopropylidene-D-glucofuranose group on thesugar residue and 3-ethoxyoxopropyl group on the ω-terminal, and inwhich a new peak based on the ethylester propionate introduced was shown(1.2, 2.3 ppm) in addition to the peak (3.6 ppm (PEO): 1.2, 1.5 ppm(isopropylidene), 3.8, 4.0, 4.2, 4.4, 4.5, 4.6, 6.0 ppm (glucofuranose)based on the polyoxyethylene chain and3,5-O-benzylidene-1,2-O-isopropylidene-D-glucofuranose group.

EXAMPLE 8

Preparation of the compound represented by the following formula##STR48##

The polyethylene oxide derivative 50 mg attained in Example 7 wasdissolved in 90 vol % trifluoracetate and left standing 40 minutes atroom temperature. After the reaction, the solvent was vacuum distilledand refined with gel filtration. The yield was 43 mg (86%). According tothe proton nuclear magnetic resonance spectra in the chloroformdeuteride of the polymer attained, this polymer was confirmed to be aheterotelechelic oligomer having a glucose group bonded at the6-position on the α-terminal and a 3-carboxyethyl group on theω-terminal, in which the peak of the ethyl ester and the peak of theisopropylidene protective group and the benzylidene protective group ofthe sugar group had completely disappeared, and which maintains the unitof polyethylene oxide (PEO).

EXAMPLE 9

Preparation of the compound represented by the following formula##STR49##

(1) The compound obtained in step (1) of Example 2 308 mg, THF 20 ml,and potassium naphthalene 0.5 mol/L-tetrahydrofuran solution 2 ml wereadded to the reaction container and agitated for 3 minutes in an argonatmosphere;6-O-potassium-3,5-O-benzylidene-1,2-O-isopropylidene-D-glucofuranose wasproduced. Ethylene oxide 5.3 g was added to this solution and agitatedfor 2 days at room temperature and 1 atm. A dimethylsulfoxide solution10 ml including N-(2-bromoethyl)phthalimide 0.4 g was added to thisreaction solution, reacted 24 hours at room temperature, and underwentchemical modification. This solution was poured into ether and thepolymer produced was precipitated. The precipitate attained was refinedby freeze drying from benzene.

(2) The polyethylene oxide derivative 50 mg attained was dissolved in 90vol % trifluoroacetate and left standing 40 minutes at room temperature.After the reaction, the solvent was vacuum distilled and refined withgel filtration. The yield was 40 mg (80%). According to the protonnuclear magnetic resonance spectra in the chloroform deuteride of thepolymer attained, this polymer maintained the polyethylene oxide (PEO)unit, the peaks of the isopropylidene protective group and thebenzylidene protective group of the sugar group disappeared completely,and a new peak based on aminoethyl group was shown (2.75, 3.06 ppm),and, thus, it was confirmed to be a heterotelechelic oligomer having aglucose group bonded in the 6-position on the α-terminal and the2-aminoethyl group on the ω-terminal.

EXAMPLE 10

Preparation of the compound represented by the following formula##STR50##

A reactor was charged with 308 mg of a compound obtained in the samemanner as in Step (1) of Example 2, 20 ml of THF and 2 ml of 0.5mol/L-tetrahydrofuran solution of naphthalene potassium, and theresulting solution was stirred for three minutes in the atmosphere ofargon, and, thus, there was formed 6-potassium-3,5-O-benzylidene-1,2-O-isopropylidene-D-glucofuranose. There was added5.3 g of ethylene oxide to this solution, which was then stirred at aroom temperature under 1 atm. After two day's reaction, 2.0 g ofmethacrylic acid anhydride was added, and the solution was furthersubjected to reaction for 48 hours at a room temperature. Then, thereaction liquid was poured into ether so that formed polymer might beprecipitated. The obtained precipitate was purified by means of freezedrying from benzene. The yield was 4.2 g (75%). The polymer obtained bymeans of gel permeation chromatography was mono-modal and had a numberaverage molecular weight of 1800.

Proton nuclear magnetic resonance spectra of the obtained polymer inchloroform deuteride taught that this polymer was a heterotelechelicoligomer which quantitatively had a unit of polyethylene oxide (PEO),had a 3,5-O-benzylidene-1,2-O-isopropylidene-D-glucofuranose residue atα-terminal, and had a methacryloyl group at ω-terminal. As for theintroduction of methacryloyl group, it was confirmed also from theobservation of the absorption of ester carbonyl near 1700 cm⁻¹ ininfrared absorption spectrum.

NMR spectrum (δ, ppm); 1.3 (s), 1.5 (s), 1.9 (s), 3.7 (s), 3.9 (s), 4.0(s), 4.2 (5), 4.4 (s), 4.6 (d), 5.6 (s)

EXAMPLE 11

Preparation of the compound represented by the following formula##STR51##

There was dissolved 50 mg of polyethylene oxide obtained in Example 10into 97 vol % acetic acid, and the resulting solution was left still for40 minutes at a room temperature. After reaction was over, the solventwas distilled off, and the solution was purified by gel filtration. Theyield was 45 mg (90%). Proton nuclear magnetic resonance spectra of theobtained polymer in chloroform deuteride taught that this polymer was aglucose which had a unit of polyethylene oxide (PEO), and in which thepeaks of benzylidene- and isopropylidene-protecting groups of sugarresidue had completely disappeared, and which quantitatively hadpolyethylene oxide chain at the hydroxyl group of 6-position. As for theremaining of methacryloyl group, it was confirmed also from theobservation of the absorption of ester carbonyl near 1700 cm⁻¹ ininfrared absorption spectrum.

NMR spectrum (δ, ppm); 1.9 (s), 3.7 (s), 4.6 (s) (β), 4.8 (s), 5.2 (s)(a), 5.6 (s), 6.2 (s)

EXAMPLE 12

Preparation of the compound represented by the following formula##STR52##

A reactor was charged with 130 mg of the compound obtained in Step (1)of Example 1, 20 ml of THF and 1 ml of 0.5 mol/L-tetrahydrofuransolution of naphthalene potassium, and the resulting solution wasstirred for three minutes in the atmoshphere of argon, and, thus, therewas formed 3-O-potassium-1,2; 5,6-di-O-isopropylidene-D-glucofuranose.There was added 3.1 g of ethylene oxide to this solution, which was thenstirred at a room temperature under 1 atm. After two day's reaction, 20ml of a solution of L-lactide dissolved in THF (2 mol/L) was added, andthe resulting solution was stirred for one hour at a room temperature sothat it might be polymerized. After the reaction was over, the reactionliquid was poured into 15 l of 2-propanol so that formed polymer mightbe precipitated. After recovered by centrifugation, the obtained polymerwas purified by means of freeze drying from benzene. The yield was 7.6 g(85.8%). The polymer obtained by means of gel permeation chromatographywas mono-modal and had a number average molecular weight of 19,000.

Proton nuclear magnetic resonance spectra of the obtained polymer inchloroform deuteride taught that this polymer was a block polymer havingboth segments of polyethylene oxide (PEO) and polylactide (PLA), whichpolymer quantitatively had a 1,2;5,6-di-O-isopropylidene-D-gluco-furanose residue at α-terminal and ahydroxyl group at ω-terminal. The segment length of PEO and PLA wererespectively 6300 and 12,900 in umber average molecular weight.

NMR spectrum (δ, ppm); 1.3 (d), 1.5 (d), 1.6 (s), 3.6 (s), 3.9 (s), 4.0(s), 4.1 (s), 4.2 (s), 4.6 (s), 5.2 (s), 5.8 (s)

EXAMPLE 13

Preparation of the compound represented by the following formula##STR53##

There was dissolved 40 mg of the block polymer obtained in Example 12into 2 ml of an 8:2 (v/v) trifluoroacetic acid-water solution, and theresulting solution was stirred for one hour at a room temperature.

The reaction aqueous solution was added dropwise to 20 ml of 2-propanolat -20° C. so that polymer might be precipitated. After centrifugation,polymer was purified by means of drying under a reduced pressure. Theyield was 31.1 mg (78.0%). As for the number average molecular weight ofthe recovered polymer, it was found by means of gel permeationchromatography and NMR that the segment length of PEO and PLA wererespectively 6300 and 11,500, and that the main chain had hardly beensevered by the treatment with 80% trifluoroacetic acid. It was found bymeans of NMR, on the other hand, that the signal of isopropylidene whichwas a protecting group of sugar residue had disappeared, and, instead, asignal of anomeric proton of reducing sugar was observed, andquantitative de-protection was confirmed.

NMR spectrum (δ, ppm); 1.6 (s), 3.6 (s), 4-5 (m), 5.2 (s), 6.1 (s) (β),6.4 (s) (α)

EXAMPLE 14

Preparation of high-molecular micelle

There was dissolved 100 mg of the polymer obtained in Example 12 into 20ml of dimethyl acetamide, and the resulting solution was dialyzedagainst water for 24 hours with use of a dialysis tube having adifferential molecular weight of 12,000-14,000 (water was replaced after3, 6 and 9 hours). When this solution was analyzed with dynamic lightscattering, there was confirmed the formation of micelle having anaverage particle size of 40 nm. The critical micelle concentration ofthis high-molecular micelle was 5 mg/l.

EXAMPLE 15

Preparation of high-molecular micelle

High-molecular micelle was prepared from the polymer obtained in Example13, in the same manner as in Example 14, and, thus, there was producedstable micelle having an average particle size of 40 nm and a criticalmicelle concentration of 5 mg/l.

INDUSTRIAL APPLICABILITY

This invention provides a mono-modal heterotelechelic oligomer orpolymer which has a polyethylene oxide segment or both a polyethyleneoxide segment and a polyester segment, and which has a sugar residue atone terminal of the segment and a different functional group at theother terminal. It is foreseen, from its constituent components, thatthe above oligomer or polymer will show excellent bioavailability.Moreover, owing to the different functional groups at the bothterminals, said oligomer or polymer is expected to be used, per se orwith use of the functional groups at the both terminals, as a carrierfor medicine or other active materials. This invention has thereforeavailability in the field of production of oligomer or polymer,medicines and diagnostic reagents.

What is claimed is:
 1. A micelle of a polyethylene oxide derivative inan aqueous solvent, said derivative being represented by the followingformula (I): ##STR54## wherein A denotes a sugar residue represented bythe following formula ##STR55## wherein one R denotes a covalent bondwith the adjacent methylene group in formula (I); and the other R groupsdenote hydrogen atom, C₁₋₅ alkyl, C₁₋₅ alkylcarbonyl or tri-C₁₋₅alkylsilyl wherein the alkyl groups are the same or different or,optionally, two of said R groups in combination, while forming an acetaltogether with the oxygen atom to which the Rs are bound, denote C₃₋₅alkylidene or benzylidene whose methine may be substituted with C₁₋₃alkyl; a denotes an integer of 0 or 1, b denotes an integer of 2 or 3,and c denotes an integer of 0 or 1,n denotes an integer of 5-10,000, Ldenotes a linkage group represented by the following formula ##STR56##wherein R¹ and R² independently denote hydrogen atom, C₁₋₆ alkyl, arylor C₁₋₃ alkylaryl, m denotes an integer of 2-10,000, X denotes a singlebond or --CH₂ CH₂ --, and when X is a single bond, Z denotes hydrogenatom, alkali metal, acryloyl, methacryloyl, cinnamoyl,p-toluenesulfonyl, allyl, carboxymethyl, carboxyethyl,ethoxycarbonylmethyl, ethoxycarbonylethyl, 2-aminoethyl, 3-aminopropyl,4-aminobutyl, vinylbenzyl, di-C₁₋₅ alkyloxy-C₂₋₃ alkyl or aldehyde-C₂₋₃alkyl.
 2. The micelle of claim 1 wherein the sugar residue A is derivedby removing a hydrogen atom from one of the R positions of amonosaccharide selected from the group consisting of glucose, galactose,mannose, fructose, ribose and xylose.
 3. The micelle of claim 1 whereinthe groups R other than the linkage of the sugar residue to theremainder of formula (I) each denote a hydrogen atom.
 4. The micelle ofclaim 1 wherein two R groups other than the linkage of the sugar residueto the remainder of formula (I) form, in combination, one or twolinkages selected from the group consisting of isopropylidene,benzylidene, 1-butylidene, 2-butylidene, 3-pentylidene and methylbenzylidene.
 5. The micelle of claim 1 wherein n denotes an integer of10-200.
 6. The micelle of claim 1 wherein X is a single bond and Zdenotes a hydrogen atom or potassium.
 7. The micelle of claim 1 whereinX is a single bond and Z denotes acryloyl, methacryloyl or p-toluenesulfonyl.
 8. The micelle of claim 1 wherein X is a single bond and Zdenotes allyl, carboxymethyl, carboxyethyl, ethoxycarbonylmethyl,ethoxycarbonylethyl, 2-aminoethyl or vinylbenzyl.
 9. The micelle ofclaim 5 wherein n is 20-50.
 10. The micelle of claim 1 wherein R¹ and R²are independently hydrogen or C₁₋₆ alkyl.
 11. The micelle of claim 10wherein R¹ and R² are independently hydrogen, methyl or isopropyl. 12.The micelle of claim 1 wherein m is 5-200.
 13. The micelle of claim 12wherein m is 10-100.
 14. The micelle of claim 1 wherein the sugarresidue A is derived by removing a hydrogen atom from one of the Rpositions of glucose or glactose, the groups R other than the linkage ofthe sugar residue to the remainder of formula (I) are either a hydrogenatom or form one or two isopropylidene and benzylidene linkages, ndenotes an integer of 10-200, m denotes an integer of 5-200, Lrepresents a formula ##STR57## and Z denotes a hydrogen atom, potassiumion, acryloyl, methacryloyl or p-toluene sulfonyl, allyl, carboxymethyl,carboxyethyl, ethoxycarbonylmethyl, ethoxycarbonylethyl or vinylbenzyl.15. A pharmaceutical carrier comprising the micelle of claim 1.